Acute adverse events of ultra-hypofractionated whole-breast irradiation after breast-conserving surgery for early breast cancer in Japan: an interim analysis of the multi-institutional phase II UPBEAT study.

BACKGROUND: The applicability of ultra-hypofractionated (ultra-HF) whole-breast irradiation (WBI) remains unknown in Japanese women. This study aimed to evaluate the safety and efficacy of this approach among Japanese women and report the results of an interim analysis performed to assess acute adverse events (AEs) and determine whether it was safe to continue this study. METHODS: We enrolled Japanese women with invasive breast cancer or ductal carcinoma in situ who had undergone breast-conserving surgery, were aged ≥ 40 years, had pathological stages of Tis-T3 N0-N1, and had negative surgical margins. Ultra-HF-WBI was delivered at 26 Gy in five fractions over one week. When the number of enrolled patients reached 28, patient registration was paused for three months. The endpoint of the interim analysis was the proportion of acute AEs of grade ≥ 2 (Common Terminology Criteria for Adverse Events v5.0) within three months. RESULTS: Of the 28 patients enrolled from seven institutes, 26 received ultra-HF-WBI, and 2 were excluded due to postoperative infections. No AEs of grade ≥ 3 occurred. One patient (4%) experienced grade 2 radiation dermatitis, and 18 (69%) had grade 1 radiation dermatitis. The other acute grade 1 AEs experienced were skin hyperpigmentation (n = 10, 38%); breast pain (n = 4, 15%); superficial soft tissue fibrosis (n = 3, 12%); and fatigue (n = 1, 4%). No other acute AEs of grade ≥ 2 were detected. CONCLUSIONS: Acute AEs following ultra-HF-WBI were within acceptable limits among Japanese women, indicating that the continuation of the study was appropriate.

A Japanese multi-institutional phase II study of moderate hypofractionated intensity-modulated radiotherapy with image-guided technique for prostate cancer.

BACKGROUND: The aim of this multi-institutional phase II study was to confirm the safety and the potential efficacy of moderately hypofractionated intensity-modulated radiotherapy (IMRT) with prostate-based image-guidance for Japanese patients. METHODS: Patients with low- or intermediate-risk localized prostate cancer were eligible. Patients with a part of high risk (having only one of the following factors, cT3a, 20 < PSA ≤ 30, or GS = 8 or 9) were also included. Hypofractionated IMRT using daily image-guided technique with prostate matching was performed with a total dose of 70 Gy in 28 fractions. Neoadjuvant hormonal therapy for 4-8 months was mandatory for patients with intermediate or high-risk prostate cancer. RESULTS: From 20 institutions, 134 patients enrolled. The median follow-up was 5.16 years (range, 1.43-6.47 years). The number of patients with low, intermediate, and high-risk prostate cancer was 20, 80, and 34, respectively. The 5-year overall, biochemical failure-free, and clinical failure-free survival was 94.5%, 96.0%, and 99.2%, respectively. The 5-year biochemical failure-free survival for patients with low-, intermediate-, and high-risk disease was 94.1%, 97.4%, and 93.9%, respectively. The incidences of grade 2 gastrointestinal (GI) and genitourinary (GU) late toxicities at 5 years were 5.3% and 5.3%, respectively. There are no acute or late toxicities ≥ grade 3. Of 124 patients who were followed for up to 5 years, the grade 2 late GU or GI toxicities were 10.5% (90% confidence intervals, 6.3-16.2%, p = 0.0958). CONCLUSION: The safety and efficacy of moderately hypofractionated IMRT with prostate-based image-guidance was confirmed among Japanese patients with prostate cancer.

Clinical outcomes of scalp or face angiosarcoma treatment with intensity-modulated radiotherapy: a multicenter study.

Combined modality therapy, including radiotherapy (RT), is a common treatment for scalp or face angiosarcoma. Although intensity-modulated radiotherapy (IMRT) can deliver homogeneous doses to the scalp or face, clinical data are limited. This multicenter study aimed to evaluate scalp or face angiosarcoma treated with definitive or post-operative IMRT. We retrospectively analyzed data from patients who received IMRT for scalp or face angiosarcoma at three institutions between January 2015 and March 2020. Local control (LC) rate, overall survival (OS), progression-free survival (PFS), recurrence patterns and toxicity were evaluated. Fifteen patients underwent IMRT during the study period. Definitive RT was performed on 10 patients and post-operative RT was performed on 5 patients. The 1-year LC rate was 85.7% (95% confidence interval [CI], 53.9-96.2%). The 1-year OS and PFS rates were 66.7% (95% CI, 37.5-84.6%) and 53.3% (95% CI, 26.3%-74.4%), respectively. Univariate analysis revealed that a clinical target volume over 500 cm3 was associated with poor LC. Distant metastasis was the most common recurrence pattern. All patients experienced Grade 2 or 3 radiation dermatitis, and five patients experienced grade ≥ 3 skin ulceration. One patient who underwent maintenance therapy with pazopanib developed Grade 5 skin ulceration. Fisher's exact test showed that post-operative RT was significantly associated with an increased risk of skin ulceration of grade ≥ 3. These results demonstrate that IMRT is a feasible and effective treatment for scalp or face angiosarcoma, although skin ulceration of grade ≥ 3 is a common adverse event in patients who receive post-operative RT.

Multicenter retrospective study of stereotactic body radiotherapy for patients with previously untreated initial small hepatocellular carcinoma.

AIM: We aimed to verify the therapeutic efficacy and safety of stereotactic body radiotherapy (SBRT) for previously untreated initial small hepatocellular carcinoma (HCC) in a multicenter, retrospective study. METHODS: Patients who underwent SBRT for HCC at the Japanese Society of Clinical Oncology (JCOG) member hospitals in Japan between July 2013 and December 2017 and met the following eligibility criteria were included: (1) initial HCC; (2) ≤3 nodules, ≤5 cm in diameter; (3) Child-Pugh score of A or B; and (4) unsuitability for or refusal of standard treatment. We analyzed the overall survival, recurrence-free survival, and cumulative incidence of local recurrence rate, and adverse events directly related to SBRT. RESULTS: Seventy-three patients with 79 lesions from 14 hospitals were analyzed. The median age was 77 years (range: 50-89 years), and the median tumor size was 23 mm (range: 6-50 mm). The median radiation dose was 40 Gy (range: 35-60 Gy) in five fractions (range: 4-8). The median follow-up period was 45 months (range: 0-103 months). The 3-year overall survival, recurrence-free survival, and cumulative incidence of local recurrence rates were 69.9% (95% CI: 58.7%-81%), 57.9% (95% CI: 45.2%-70.5%), and 20.0% (95% CI: 11.2%-30.5%), respectively. Four cases (5.5%) of adverse events of grade 3 or higher were reported: three cases of grade 3 and one case of grade 4 (duodenal ulcer). No grade 5 toxicities were observed. CONCLUSION: SBRT is a promising treatment modality, particularly for small HCCs, as they are not suitable for standard treatment.

Perianal Bowen's disease treated with radiotherapy preserving anal function with a unique skin reaction considered as 'tumoritis'.

Bowen's disease (BD) is a form of intraepidermal squamous cell carcinoma (SCC), and it occasionally occurs on the perianal site. BD is often treated with surgical excision; however, sometimes surgical excision for perianal BD cannot preserve anal function. We report the case of a 72-year-old man presenting with perianal pain and BD. He was treated with Radiotherapy (RT) and preserved his normal anal sphincter function without any recurrence or late adverse event. Moreover, we observed the unique skin reaction called 'tumoritis', which is characterized by mucosal inflammation. Tumoritis indicates the true extent of the tumor and evaluating the tumor or lesion size based on the extent of tumoritis when performing RT is important.

Multi-institutional phase II study of ultra-hypofractionated whole-breast irradiation after breast-conserving surgery for breast cancer in Japan: Kyoto Radiation Oncology Study Group (UPBEAT study).

PURPOSE: The UK-FAST-Forward study showed that ultra-hypofractionated whole-breast irradiation (ultra-HF-WBI) involving five fractions of 26 Gy radiation over 1 week was not inferior to HF-WBI. However, it is not used in Japan due to safety concerns. In April 2022, we commenced a multi-institutional, single-arm, phase II trial. Our aim is to confirm the safety of ultra-HF-WBI after breast-conserving surgery (BCS) for breast cancer in Japanese women. METHOD: We plan to enroll 98 patients from 13 institutions. The primary endpoint is the proportion of late adverse events of grades ≥2 within 3 years. DISCUSSION: We believe that this highly promising clinical study can positively impact the Japanese guidelines for breast cancer treatment. The results will help us decide whether or not ultra-HF-WBI can be used as a more convenient alternative to WBI. REGISTRATION NUMBER AND DATE: This trial was registered in the UMIN Clinical Trials Registry (UMIN000047080) on March 4, 2022.

Optimal Clinical Target Volume of Radiotherapy Based on Microscopic Extension around the Primary Gross Tumor in Non-Small-Cell Lung Cancer: A Systematic Review.

A crucial issue in radical radiation therapy for non-small-cell lung cancer is how to define the clinical target volume (CTV). Although the scope of microscopic extension (ME) and microscopic proximal bronchial extension (PBE) from a primary tumor should be considered when defining the CTV, there has been limited research on ME and PBE. Therefore, we conducted this systematic review. The PubMed, ICHUSHI (Japanese database), and Cochrane Library databases were searched, and 816 articles were initially retrieved. After primary and secondary screenings, eight articles were ultimately selected. The results of this systematic review suggest the importance of a 0 mm margin in stereotactic radiotherapy for early-stage cancer and a 5-8 mm margin in curative irradiation for locally advanced cancer. Regarding PBE, this review yielded the conclusion that it is appropriate to consider the addition of an approximately 15 mm margin from the bronchial vasculature. Although there were few articles with a high level of evidence, this systematic review enabled us to collate results from previous studies and to provide recommendations, to some extent, regarding the CTV margin in the current clinical environment, where high-precision radiation therapy, such as image-guided radiotherapy and intensity-modulated radiotherapy, is predominant.

Multi-institutional feasibility study of intensity-modulated radiotherapy with chemotherapy for locally advanced non-small cell lung cancer.

BACKGROUND: This multi-institutional clinical trial evaluated the feasibility of intensity-modulated radiotherapy (IMRT) for patients with locally advanced non-small cell lung cancer (NSCLC). METHODS: The major inclusion criteria were clinical stage III NSCLC, age 20-74 years, and Eastern Cooperative Oncology Group performance status 0-1. Patients were treated with either cisplatin + S-1 (CS; four cycles every 4 weeks) or carboplatin + paclitaxel (CP; administered weekly with thoracic radiotherapy [RT], plus two consolidation cycles) concurrently with IMRT (60 Gy in 30 fractions). The primary endpoint was a treatment completion rate, defined as at least two cycles of CS or five cycles of CP during IMRT and completing 60 Gy IMRT within 56 days after the start of treatment, assumed its 90% confidence interval exceeds 60%. RT quality assurance was mandatory for all the patients. RESULTS: Twenty-two patients were registered. One patient withdrew due to pulmonary infection before starting treatment. RT plans were reviewed and none was judged as a protocol violation. Grade 2 and 3 pneumonitis occurred in four (19%) and one (5%) patients, respectively. Seventeen patients met the primary endpoint, with a treatment completion rate of 77.3% (90% confidence interval [CI] 58.0%-90.6%). Four patients failed to complete chemotherapy due to chemotherapy-related adverse events, but 20 patients completed IMRT. There were no treatment-related deaths. The 2-year progression-free and overall survival rates were 31.8% (95% CI 17.3%-58.7%) and 77.3% (95% CI 61.6%-96.9%), respectively. CONCLUSION: The treatment completion rate did not meet the primary endpoint, but 20 of 22 patients completed IMRT.

Concurrent Chemoradiotherapy With Weekly Low-Dose Cisplatin for Japanese Patients With Head and Neck Squamous Cell Carcinoma.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) with tri-weekly high-dose cisplatin (HDC) is considered the standard regimen. However, due to significant toxicity, various weekly low-dose schedules have been increasingly used. We investigated the tolerability and survival of patients with head and neck squamous cell carcinoma (HNSCC) who underwent CCRT with low-dose weekly cisplatin (LDC) for Japanese population. METHODS: A retrospective review was conducted among patients with HNSCC who were treated with CCRT/LDC in our institute. Ninety-five patients who met the criteria were enrolled in this study. We evaluated the cycle and cumulative cisplatin dose, completion rate of radiotherapy, adverse events, and survival outcome. RESULTS: The mean cycles and cumulative cisplatin dose were 4.7 cycles and 187 mg/m2. All patients completed planned dose of radiation without prolonged breaks. Leucopoenia was the most frequent dose-limiting factor and 44% patients developed grade 3 or 4 toxicity. The 2-year overall survival and recurrence-free survival were 93% and 74%, respectively. The significant differences of survival outcomes between the patients with total cisplatin dose (⩾200 mg and <200 mg) or among age distribution (35-55, 56-75, and ⩾76) were not observed. CONCLUSIONS: Concurrent chemoradiotherapy/LDC can be safely administered with acceptable toxicity and survival outcome even if the patients with higher age, lower eGFR, and so on.

Multicenter prospective study of stereotactic body radiotherapy for previously untreated solitary primary hepatocellular carcinoma: The STRSPH study.

AIM: To prospectively evaluate the efficacy and safety of stereotactic body radiotherapy (SBRT) for patients with previously untreated solitary primary hepatocellular carcinoma (HCC). METHODS: The main eligibility criteria included the following: (1) primary solitary HCC; (2) no prior treatment for HCC; (3) Child-Turcotte-Pugh score of seven or less; and (4) unsuitability for or refusal of surgery and radiofrequency ablation (RFA). The prescribed dose of SBRT was 40 Gy in five fractions. The primary endpoint was 3-year overall survival (OS); the secondary endpoints included local progression-free survival (LPFS), local control (LC), and adverse events. The accrual target was 60 patients, expecting a 3-year OS of 70% with a 50% threshold. RESULTS: Between 2014 and 2018, 36 patients were enrolled; enrollment was closed early because of slow accrual. The median tumor size was 2.3 cm. The median follow-up at the time of evaluation was 20.8 months. The 3-year OS was 78% (95% confidence interval [CI]: 53%-90%). The 3-year LPFS and LC proportion were 73% (95% CI: 48%-87%) and 90% (95% CI: 65%-97%), respectively. Grade 3 or higher SBRT-related toxicities were observed in four patients (11%), and grade five toxicities were not observed. CONCLUSIONS: This study showed acceptably low incidence of SBRT-related toxicities. LC and OS after SBRT were comparable for previously untreated solitary HCC for patients unfit for resection and RFA. Although a definitive conclusion cannot be drawn by this study, the promising results indicate that SBRT may be an alternative option in the management of early HCC.

Difficulty in distinguishing radiation-induced prostate sarcoma from radiation mucositis in a patient with persistent urinary retention and hematuria after prostate cancer radiotherapy.

Urinary retention and hematuria owing to radiation-induced mucositis are occasional late adverse events in patients with prostate cancer. Moreover, radiation-induced secondary malignancies are late adverse events, although they are extremely rare. Herein, we describe a case of radiation-induced secondary malignancy of the prostate that was initially difficult to distinguish from radiation mucositis. A 74-year-old man with prostate cancer underwent brachytherapy and external beam radiotherapy 9 years ago. Twenty-eight months after irradiation, he presented with urinary retention and hematuria owing to radiation mucositis and underwent transurethral resection of the prostate. At 89 months after irradiation, the patient again showed urinary retention and hematuria. The cause of urinary retention and hematuria could not be identified on cystoscopy. Despite receiving medications, the patient's symptoms did not improve. Therefore, transurethral fulguration was performed, and prostate biopsy revealed spindle cell sarcoma. A diagnosis of radiation-induced undifferentiated pleomorphic/spindle cell sarcoma was made, and the patient underwent total cystectomy and construction of the ileal conduit. Two weeks after the surgery, computed tomography revealed peritoneal dissemination. The patient died 5 weeks after the surgery. The case findings indicate that clinicians should consider the possibility of radiation-induced secondary malignancy; moreover, thorough pathological examination of the prostate with CT and MRI is important to distinguish RISM from radiation mucositis even if no tumors are found on cystoscopy.

Prevalence of hypothyroidism among patients with breast cancer treated with radiation to the supraclavicular field: a single-centre survey.

PURPOSE: We investigated the prevalence of hypothyroidism (HT) in patients with breast cancer who received radiation therapy to the supraclavicular (SC) field to evaluate the effect of radiation on thyroid. METHODS: Between April 2007 and May 2016, consecutive patients with invasive breast cancer who received SC radiation were recruited. Thyroid-stimulating hormone (TSH) and free thyroxine (fT4) were measured between April and August 2016. On the basis of the radiation-planning CT images, thyroid volume was calculated and dose-volume parameters were estimated. The endpoints were the prevalence of HT as determined by high levels of TSH and low levels of fT4 in serum, and the prevalence of subclinical HT, determined by high-serum TSH and normal fT4. RESULTS: Among the 68 consecutive patients, 26 were excluded from evaluation (10 patients died, 6 had a history of previous thyroid disease and 10 were lost to follow-up). One (2.4%) and six (14.3%) of these patients had HT and subclinical HT, respectively, with a mean TSH level of 8.27 µU/mL. By univariate analysis, a predictive factor of HT and subclinical HT was a thyroid volume <8 cm3 (OR 6.44, 95% CI 1.14 to 36.6; p=0.043). Multivariate analysis also showed an association between thyroid volume <8 cm3 and HT or subclinical HT (OR 18.48, 95% CI 1.48 to 230.86; p=0.024). CONCLUSIONS: The prevalence of HT in patients with breast cancer studied was relatively low. Although thyroid volume appeared to be a predictive marker of HT in this cohort, further prospective evaluation is needed.

Modifying the planning target volume to optimize the dose distribution in dynamic conformal arc therapy for large metastatic brain tumors.

PURPOSE: When treating large metastatic brain tumors with stereotactic radiotherapy (SRT), high dose conformity to target is difficult to achieve. Employing a modified planning target volume (mPTV) instead of the original PTV may be one way to improve the dose distribution in linear accelerator-based SRT using a dynamic conformal technique. In this study, we quantitatively analyzed the impact of a mPTV on dose distribution. MATERIALS AND METHODS: Twenty-four tumors with a maximum diameter of >2 cm were collected. For each tumor, two plans were created: one used a mPTV and the other did not. The mPTV was produced by shrinking or enlarging the original PTV according to the dose distribution in the original plan. The dose conformity was evaluated and compared between the plans using a two-sided paired t test. RESULTS: The conformity index defined by the Radiation Therapy Oncology Group was 1.34 ± 0.10 and 1.41 ± 0.13, and Paddick's conformity index was 0.75 ± 0.05 and 0.71 ± 0.06, for the plans with and without a mPTV, respectively. All of these improvements were statistically significant (P < 0.05). CONCLUSION: The use of a mPTV can improve target conformity when planning SRT for large metastatic brain tumors.

Treatment of malignant melanoma with nivolumab and vemurafenib combined with hypofractionated radiation therapy.

Management of metastatic malignant melanoma is challenging. Although several new systemic therapies for metastatic malignant melanoma have recently been developed, some patients still also require radiation therapy (RT) for palliative care. However, the safety and efficacy of combining use of novel drugs with RT remain unclear. Here, we report treating a patient with rapidly growing malignant melanoma with a programmed cell death protein 1 (PD-1) inhibitor and a BRAF inhibitor together with 60 Gy of hypofractionated RT without severe adverse effects. The tumor within the radiation field exhibited a more marked response than that outside it. A combination of RT with an anti-PD-1 antibody or a BRAF inhibitor may, therefore, be a useful and tolerable approach to treating metastatic BRAF-mutant melanoma.

Stereotactic Body Radiotherapy for Synchronous Primary Lung Cancer: Clinical Outcome of 18 Cases.

BACKGROUND: Previous reports have shown that curative surgical approaches for synchronous primary lung cancer (SPLC) yielded excellent treatment outcomes. However, patients with SPLC are often unsuitable for such surgery as a result of poor general condition or other medical comorbidities. The effectiveness and feasibility of stereotactic body radiotherapy (SBRT) as a definitive treatment for SPLC are not well understood. PATIENTS AND METHODS: We retrospectively reviewed the records of the patients who received lung SBRT between July 2007 and December 2012 at our institution and identified patients with SPLC. The clinical outcome was analyzed for each patient. The first progression site was classified as local, regional, distant, or new primary lung cancer. RESULTS: A total of 18 patients were eligible. Fifteen patients received SBRT for both lesions, and 3 patients received surgery for one tumor and SBRT for the other. The median follow-up time was 34.3 months (range, 12.2-64.7 months). The median overall and progression-free survival was 45.6 months (95% confidence interval [CI] 21.0-60.6) and 25.3 months (95% CI, 13.1-50.6 months), respectively. The 3-year overall survival and progression-free survival rates were 69.1% (95% CI, 40.7-85.9) and 43.2% (95% CI, 20.2-64.4), respectively. Eleven patients (61%) experienced disease progression. The first progression site was local in 4 (22%), regional in 5 (28%), distant in 3 (17%), and new primary lung cancer in 2 patients (11%). Grade 3 radiation pneumonitis was observed in 2 patients (11%). CONCLUSION: SBRT for SPLC is a highly effective local treatment with limited toxicity, although the progression rate seems relatively high.

Therapeutic outcomes of neoadjuvant and concurrent androgen-deprivation therapy and intensity-modulated radiation therapy with gold marker implantation for intermediate-risk and high-risk prostate cancer.

OBJECTIVES: To investigate the therapeutic outcomes of neoadjuvant and concurrent androgen-deprivation therapy and intensity-modulated radiation therapy with gold marker implantation for intermediate- and high-risk prostate cancer. METHODS: This was a retrospective study of 325 patients with intermediate- or high-risk prostate cancer according to the National Comprehensive Cancer Network guidelines who underwent androgen-deprivation therapy and intensity-modulated radiation therapy (76 Gy) after gold marker implantation between 2001 and 2010. RESULTS: The 5-year distant metastasis-free survival rate was significantly lower for very high-risk patients than for intermediate- and high-risk patients (82.6% vs 99.4% and 96.5%, respectively; P < 0.01). The 5-year biochemical relapse-free survival rates significantly declined with increasing prostate cancer risk (P < 0.01), and were 95.9%, 87.2%, and 73.1% for the intermediate-risk, high-risk and very high-risk patients, respectively. Acute genitourinary and gastrointestinal toxicity grade ≥3 were not observed in any of the patients. Late grade 3 genitourinary toxicity occurred in 0.3% of patients. CONCLUSION: Combination androgen-deprivation therapy and 76-Gy intensity-modulated radiation therapy with gold marker implantation offers good therapeutic outcomes with few serious complications in patients with intermediate- and high-risk prostate cancer.

Phase II study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer.

PURPOSE: S-1 is an oral fluoropyrimidine derivative that has demonstrated favorable antitumor activity in patients with metastatic pancreatic cancer. The aim of this study was to evaluate safety and efficacy of S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. METHODS AND MATERIALS: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day at a dose of 80 mg/m(2)/day from day 1 to 14 and 22 to 35. Two weeks after the completion of chemoradiotherapy, maintenance chemotherapy with S-1 was administered for 28 days every 6 weeks until progression. RESULTS: Thirty-four patients were enrolled in this study. The most common Grade 3 toxicities during chemoradiotherapy were anorexia (24%) and nausea (12%). The overall response rate was 41% (95% confidence interval, 25%-58%) and overall disease control rate (partial response plus stable disease) was 97%. More than 50% decrease in serum CA 19-9 was seen in 27 of 29 evaluable patients (93%). The median progression-free survival was 8.7 months. The median overall survival and 1-year survival rate were 16.8 months and 70.6%, respectively. CONCLUSIONS: Oral S-1 and concurrent radiotherapy exerted a promising antitumor activity with acceptable toxicity in patients with locally advanced pancreatic cancer. This combination therapy seems to be an attractive alternative to conventional chemoradiotherapy using 5-fluorouracil infusion.